Zhou et al.

Journal of Neuroinflammation (2016) 13:141

DOI 10.1186/s12974-016-0607-6

REVIEW Open Access

Interleukin-6: an emerging regulator of

pathological pain
Ya-Qun Zhou1, Zheng Liu2, Zhi-Heng Liu3, Shu-Ping Chen1, Man Li4, Allahverdi Shahveranov5, Da-Wei Ye5*
and Yu-Ke Tian1

Abstract
Interleukin-6 is an inflammatory cytokine with wide-ranging biological effects. It has been widely demonstrated that
neuroinflammation plays a critical role in the development of pathological pain. Recently, various pathological pain
models have shown elevated expression levels of interleukin-6 and its receptor in the spinal cord and dorsal root
ganglia. Additionally, the administration of interleukin-6 could cause mechanical allodynia and thermal hyperalgesia,
and an intrathecal injection of anti-interleukin-6 neutralizing antibody alleviated these pain-related behaviors. These
studies indicated a pivotal role of interleukin-6 in pathological pain. In this review, we summarize the recent progress in
understanding the roles and mechanisms of interleukin-6 in mediating pathological pain associated with bone cancer,
peripheral nerve injury, spinal cord injury, chemotherapy-induced peripheral neuropathy, complete Freund’s adjuvant
injection, and carrageenan injection. Understanding and regulating interleukin-6 could be an interesting lead to novel
therapeutic strategies for pathological pain.
Keywords: Interleukin-6, Bone cancer pain, Neuropathic pain, Inflammatory pain

Background interleukin-6 (IL-6), may play a critical role in the develop-

Pathological pain is characterized by a low threshold and
an exaggerated response to noxious stimuli, and it can be
categorized as cancer pain, neuropathic pain, or inflamma-
tory pain [1, 2]. Although physiological pain is essential for
the elimination of damaging stimuli, pathological pain sig-
nificantly affects the quality of life [3–5]. Currently, patho-
logical pain is thought to be mainly induced by a
combination of peripheral drives and central processing
[6–9]. Despite growing knowledge of the mechanisms of
pathological pain, this type of pain still represents a major
challenge in clinical practice and basic science. Cytokines
have been reported to participate in the regulation of nu-
merous cellular functions including the inflammatory re-
sponse and expression of cell surface proteins [10–12]. In
addition, we previously reported that several cytokines
could potentially serve as targets for the management of
bone cancer pain (BCP) [13–19]. Recently, mounting evi-
dence has suggested that one cytokine in particular,
* Correspondence: dy0711@gmail.com
5
Cancer Center, Tongji Hospital, Tongji Medical College, Huazhong University
of Science and Technology, Wuhan, China
Full list of author information is available at the end of the article
ment of pathological pain [20–24].
IL-6 is an inflammatory cytokine with wide-ranging bio-
logical effects. It was first described as B-stimulatory factor
2, which induces B lymphocytes to produce immuno-
globulin [25]. IL-6 exerts its biological effect on target cells
by interacting with the non-signaling membrane-bound
IL-6 receptor (mIL-6R) [26, 27]. The IL-6 and mIL-6R
complex then associates with the signal transducing mem-
brane protein gp130, promoting its dimerization and the
subsequent activation of intracellular signaling including
the Janus-activated kinase/signal transducer activator of
transcription (JAK/STAT), mitogen-activated protein
kinase/extracellular signal-regulated kinase (MAPK/ERK),
and phosphatidylinositol 3-kinase/protein kinase B (PI3K/
Akt) signaling pathways [28–30]. This manner of IL-6 sig-
naling is often referred to as “classical IL-6 signaling.”
gp130 is expressed by almost all cells in the body, whereas
the mIL-6R has a highly restricted expression profile, and
is mainly expressed by hepatocytes, neutrophils, mono-
cytes/macrophages and certain other leukocytes [31, 32].
Only cells expressing mIL-6R can bind and respond to IL-
6. Thus, until the discovery of a naturally occurring soluble
form of IL-6R (sIL-6R), it was difficult to understand how

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Zhou et al. Journal of Neuroinflammation (2016) 13:141
IL-6 could elicit wide-ranging biological responses by
interacting with a limited number of cell types. sIL-6R has
been found in various body fluids and has been shown to
be generated by two independent mechanisms: limited
proteolytic cleavage from mIL-6R and translation from a
differentially spliced messenger RNA (mRNA) [33–35]. A
complex comprising IL-6 and sIL-6R is also able to bind
to gp130 and to initiate intracellular signaling [36, 37].
Through this so-called “trans-signaling” mechanism, IL-6
is capable of stimulating cells that lack endogenous mIL-
6R [38]. Additionally, it has been shown that the soluble
form of gp130 (sgp130) exclusively inhibits IL-6 responses
mediated via the IL-6/sIL-6R complexes (i.e., trans-
signaling) and does not affect stimulation via mIL-6R (i.e.,
classical IL-6 signaling) [39–41]. Therefore, sgp130 can be
used as a molecular tool to discriminate between classical
signaling and trans-signaling.
Various pathological pain models have shown elevated
expression levels of IL-6, IL-6R, and gp130 in the spinal
cord and dorsal root ganglia (DRG). Additionally, the
administration of IL-6 could cause mechanical allodynia
or thermal hyperalgesia, and an intrathecal injection of
anti-IL-6 neutralizing antibody alleviated these pain-
related behaviors. Furthermore, IL-6 was reported to be
intimately linked to nociceptive plasticity by enhancing
translation in sensory neurons [42, 43]. IL-6 was also dem-
onstrated to contribute to nociceptor sensitization and
central sensitization [44–47]. These studies suggested an
important role of IL-6 in pathological pain, indicating that
the targeting of IL-6 or its receptor may reveal novel
therapeutic interventions for the management of patho-
logical pain. Moreover, humanized anti-IL-6R monoclonal
antibody has exhibited excellent efficacy and safety against
numerous diseases [48–50]. Therefore, here we review the
current evidence of the role of IL-6 in the generation of
pathological pain caused by bone cancer, peripheral nerve
injury, spinal cord injury, chemotherapy-induced periph-
eral neuropathy, complete Freund’s adjuvant (CFA) injec-
tion, or carrageenan injection.
IL-6 and cancer pain
Advanced prostate, lung, and breast cancer frequently
metastasize to the bone, which causes 75–90 % of these pa-
tients to experience severe pain [51–53]. There is growing
body of evidence demonstrating that IL-6 plays a vital role
in various aspects of tumor behaviors including cell prolif-
eration, migration, invasion, differentiation, and angiogen-
esis [54–57]. In this review, we focus on the critical role of
IL-6 in pain caused by bone metastasis.
The involvement of IL-6 in BCP was first reported by
Dong et al. [58], who used a rat model of BCP. In this
study, the reverse transcription polymerase chain reaction
(RT-PCR) results showed that the mRNA levels of IL-6
were considerably increased on 16 days after tumor cell
Page 2 of 9
implantation (TCI). Furthermore, intrathecal administra-
tion of EphB1-Fc significantly suppressed the mRNA levels
of IL-6 in the spinal cord, indicating a downstream role
of IL-6 in the analgesic effect of EphB1-Fc. In another
study, immunohistochemistry and enzyme-linked immuno-
sorbent assay (ELISA) work revealed that spinal IL-6 levels
were significantly increased on day 12 after TCI [59]. It was
found that propentofylline (PPF), a glial modulating agent,
could alleviate pain hypersensitivity after TCI; in addition,
the intrathecal injection of PPF markedly inhibited the ex-
pression of IL-6. Recently, it was shown that the intrathecal
injection of tanshinone IIA, an ingredient in a traditional
Chinese medicine, attenuated thermal hyperalgesia in a
mouse model of BCP by inhibiting the release of pro-
inflammatory cytokines [60]. More recently, Lu et al. [61]
provided evidence for the persistent involvement of inflam-
mation in the development of BCP; JWH-015, a selective
cannabinoid receptor agonist, reduced the expression of
pro-inflammatory cytokines in a time-dependent manner,
thereby exerting an anti-nociceptive effect. Using condi-
tional knockout mice lacking gp130 specifically in nocicep-
tors, Andratsch et al. [62] uncovered that gp130 expressed
in peripheral pain sensing neurons is critically required for
the development of cancer pain. In addition, Quarta et al.
[63] have shown the first genetic evidence that gp130 in
Nav1.8 expressing primary afferents contributes to the
maintenance of nociceptor sensitization in a mouse model
of cancer pain. They found that mice with a null mu-
tation of gp130 (gp130−/−) showed signs of nociceptor
sensitization and hypersensitivity to mechanical stimuli in
the early stage. However, gp130−/− mice significantly re-
covered from hypersensitivity in the later stage, indicating
that gp130 signal transducer plays a substantial role in
regulating mechanical hypersensitivity particularly in the
maintenance phase of cancer pain. The findings from the
studies above implicate a role of IL-6 in the progression of
cancer pain. However, the underlying mechanisms of IL-6
in the development of BCP were not investigated until
Fang et al. [20]. Using RT-PCR and Western blotting, the
expression levels of IL-6 and sIL-6R in the ipsilateral L4
and L5 DRG were found to be remarkably higher in BCP
rats than in sham rats. Additionally, the intrathecal ad-
ministration of FIL-6, a mixture of IL-6 and sIL-6R, in-
duced hyperexcitability of nociceptive DRG neurons
acutely isolated from naive rats and caused mechanical
allodynia and thermal hyperalgesia in naive rats, suggest-
ing that increased IL-6 contributed to the pathogenesis of
BCP. Furthermore, both pretreatment and posttreatment
with sgp130, a potent IL-6/sIL-6R trans-signaling inhibi-
tor, remarkably attenuated the bone cancer induced over-
excitability of DRG neurons and hyperalgesia in BCP rats,
indicating that IL-6/sIL-6R trans-signaling was involved in
the development of BCP by inducing DRG neurons hyper-
excitability. More importantly, they found that transient
Zhou et al. Journal of Neuroinflammation (2016) 13:141
receptor potential vanilloid channel type 1 (TRPV1) was
the downstream target on which the enhanced expression
of IL-6 in DRG neurons exerted its effects associated with
the development of BCP. Activation of the JAK/PI3K sig-
naling pathway was required for both the FIL-6-induced
functional upregulation of TRPV1 in DRG neurons and
pain hypersensitivity in naive rats. This study provided
various lines of evidence for a novel intracellular pathway,
the IL-6/JAK/PI3K/TRPV1 signaling cascade, which may
underlie the development of peripheral sensitization and
BCP.
IL-6 and neuropathic pain
Neuropathic pain is a chronic pain condition caused by
a primary lesion in or dysfunction of the nervous system
and is characterized by spontaneous and evoked pain
[64–66]. This type of pain is commonly observed in pa-
tients with cancer, diabetic peripheral neuropathy, herpes
infection, spinal cord injury (SCI), or multiple sclerosis
[67, 68]. Although there is no systematic classification sys-
tem, neuropathic pain could be classified based on the eti-
ology of the insult to the nervous system or the
anatomical distribution of the pain [69]. Various animal
models have been established to explore the mechanisms
of neuropathic pain of different etiologies, including per-
ipheral nerve injury, SCI, and chemotherapy-induced per-
ipheral neuropathy. Using these animal models, a great
deal of basic research has been performed to elucidate the
mechanisms of neuropathic pain, which are complex and
involve both peripheral and central pathophysiological
phenomena. Following peripheral nerve injury, A-δ fiber
and C-fiber primary afferent neurons become abnormally
sensitive and develop pathological spontaneous activity,
leading to peripheral sensitization [70]. This sensitization
triggers the production of mediators, alteration of ion
channels, and sprouting of nerves endings. These activities
provoke secondary changes in central sensory processing,
thereby contributing to spinal cord hyperexcitability and
central sensitization [71]. Recently, converging lines of evi-
dence have indicated that IL-6 plays a critical role in
neuropathic pain caused by peripheral nerve injury, SCI,
and chemotherapy-induced peripheral neuropathy.
IL-6 and peripheral nerve injury
Most studies have used an animal model of peripheral
nerve injury to explore the relationship between IL-6
and neuropathic pain. A growing body of research has
demonstrated that IL-6 plays a role in the pathogenesis
of neuropathic pain. The involvement of IL-6 in periph-
eral neuropathy was first found in a rat model of sciatic
cryoneurolysis (SCN), in which the sciatic nerve was fro-
zen to induce nerve injury [72]. The immunohistochemi-
cal data resulting from this model showed that IL-6-like
immunoreactivity was significantly higher in both the
Page 3 of 9
dorsal and ventral horns in SCN rats than in those of
normal rats. Furthermore, intrathecal administration of
recombinant human IL-6 could mimic and even potenti-
ate pain behavior after SCN. These results provided evi-
dence that IL-6 may be involved in the development of
neuropathic pain following SCN. In a subsequent study,
they demonstrated that IL-6 mRNA was significantly ele-
vated in both the dorsal and ventral horns in a neuro-
pathic pain model of spinal nerve cryoneurolysis and
spinal nerve tight ligation using in situ hybridization and a
digoxigenin-labeled oligonucleotide [73]. In addition, they
further demonstrated that an intrathecal injection of anti-
IL-6 antibody could attenuate L5 spinal nerve transection-
induced mechanical allodynia [74], providing further evi-
dence for the role of central IL-6 in the etiology of mech-
anical allodynia following peripheral nerve injury. In
another study, Ramera et al. [75] reported that spinal
nerve lesion-induced mechanical allodynia was attenuated
and delayed in IL-6 knockout mice, indicating a role of
IL-6 in the initiation of neuropathic pain. Similar results
were reported in IL-6−/− mice using chronic constriction
injury (CCI) model [76]. Using in situ hybridization,
Brazda et al. [77] were the first group to show that IL-6
and IL-6R synthesis was increased in remote cervical
DRG not associated with the nerve injury following CCI.
They found that unilateral CCI induced the bilateral eleva-
tion of IL-6 and IL-6R mRNAs not only in L4–L5 DRG
but also in remote cervical DRG, suggesting a general
neuro-inflammatory reaction of the nervous system to
local nerve injury. They further confirmed their hypothesis
in a subsequent study [78].
The above studies demonstrated the participation of
IL-6 in the pathogenesis of peripheral nerve injury-
induced neuropathic pain. However, the underlying mo-
lecular and cellular mechanisms were not investigated.
In an in vivo and in vitro study, Ma et al. [79] reported
the involvement of prostaglandin E2 (PGE2) in the up-
regulated expression of IL-6 by invading macrophages
following partial sciatic nerve ligation (PSNL). The im-
munostaining results of the in vivo study confirmed the
dramatically increased number of IL-6-immunoreactive
cells in the injured nerve of PSNL rats. The in vitro re-
sults showed that the levels of both PGE2 and IL-6 re-
leased from cultured cells derived from injured nerves
were significantly increased, as well as that these elevated
levels could be suppressed by non-selective and selective
COX2 inhibitors. Interestingly, although PGE2 treatment
did not remarkably increase the level of IL-6 released from
cultured cells derived from uninjured nerve, it did increase
the level of IL-6 released from injured nerve-derived cells
in a concentration- and time-dependent manner. More-
over, both a selective PGE2 receptor 4 (EP4) antagonist
(L-161982) and a protein kinase C (PKC) inhibitor
(calphostin C) dramatically suppressed IL-6 release. These
Zhou et al. Journal of Neuroinflammation (2016) 13:141
findings suggested that PGE2 was involved in mediating
the upregulation of IL-6 occurring in invading macro-
phages via the EP4 receptor and the PKC pathway. In a
subsequent study, they also demonstrated the role of
PGE2 in the synthesis of IL-6 in primary sensory neurons
following PSNL [80]. The in vivo data showed that injured
nerve-derived PGE2 contributed to the de novo synthesis
of IL-6 in damaged medium and large size DRG neurons
following PSNL by activating the EP4 receptors. The in
vitro data showed that EP4 receptor, PKA, PKC, ERK/
MAPK, CREB, and NF-kB signaling pathways were in-
volved in PGE2-induced IL-6 production in DRG neurons.
These results provided evidence that facilitating the de
novo synthesis of IL-6 in injured medium and large size
DRG neurons was a new mechanism underlying the role
of injured nerve-derived PGE2 in the development of
neuropathic pain.
As IL-6 mainly activates the JAK/STAT transduction
pathway, Dominguez et al. [81] investigated the possible ac-
tivation of this signaling system in the spinal cord using an
SNL model. It was shown that phospho-STAT3 (p-STAT3)
in microglial cells of the spinal cord dorsal horn was signifi-
cantly increased in SNL rats compared with sham rats and
that inhibiting the STAT3 pathway attenuated both mech-
anical allodynia and thermal hyperalgesia in SNL rats. In
line with previous studies, they found a massive induction
of IL-6 mRNA expression in DRG and an increased con-
centration of IL-6 in the spinal cord dorsal horn. In
addition, the intrathecal injection of anti-rat IL-6 antibodies
prevented the SNL-induced accumulation of p-STAT3 in
the spinal cord. Together, these data suggest that IL-6 plays
a major role in the activation of the spinal JAK/STAT3
pathway after SNL and that this transduction pathway par-
ticipates in the development of neuropathic pain.
It was reported that tumor necrosis factor-α (TNF-α),
which binds to tumor necrosis factor receptor 1 (TNFR1)
and induces NF-kB and p38 MAPK activation, was also
upregulated following peripheral nerve injury [82, 83].
Therefore, Lee et al. [84] investigated whether TNFR1 reg-
ulates IL-6 expression through NF-kB or p38 MAPK acti-
vation in the spinal cord and DRG using a CCI model.
They found that the CCI-induced upregulation of IL-6 ex-
pression was suppressed by intrathecal injection of a
TNFR1 antisense oligonucleotide and an NF-kB decoy, but
not by a p38 MAPK inhibitor, suggesting that TNFR1 in-
duces IL-6 upregulation through NF- kB activation, but
not p38 MAPK activation, in a CCI model. In a subsequent
study, they further examined whether IL-6 regulates
CX3CR1 expression through p38 MAPK activation in the
spinal cord of CCI rats [21]. It was shown that CX3CR1 ex-
pression and p38 MAPK activation in the ipsilateral spinal
dorsal horn were significantly increased following CCI and
that an intrathecal injection of anti-IL-6 neutralizing anti-
body dramatically decreased both CX3CR1 expression and
Page 4 of 9
p38 MAPK activation. Additionally, naïve rats treated with
exogenous recombinant rat IL-6 (rrIL-6) showed increased
spinal CX3CR1 expression and p38 MAPK activation. Fur-
thermore, treatment with a p38 MAPK-specific inhibitor,
SB203580, suppressed the increase in CX3CR1 expression
induced by either CCI or rrIL-6 treatment. These results
indicated that IL-6 induces microglial CX3CR1 expression
in the spinal cord after peripheral nerve injury through p38
MAPK activation, which demonstrates a new mechanism
of neuropathic pain.
Several drugs have been reported to alleviate neuro-
pathic pain, and this alleviation was accompanied by de-
creased serum level of IL-6 [85–87]. Recently, the clinical
involvement of IL-6 in peripheral nerve injury-induced
pain was also reported. Ohtori et al. [88] found that an
epidural injection of an anti-IL-6R monoclonal antibody,
tocilizumab, onto the spinal nerve alleviated radicular leg
pain, numbness, and low back pain without causing ad-
verse events in 60 patients with lumbar spinal stenosis-
induced sciatica.
IL-6 and spinal cord injury
Approximately 70 % of SCI patients have been reported to
have chronic pain, and the pathogenesis of which remains
largely unknown [89, 90]. Guptarak et al. [22] conducted a
study to investigate the role of IL-6 in spinal cord injury
pain (SCIP) using a clinically relevant rat contusion model.
They found that only SCI rats that developed mechanical
allodynia showed elevated IL-6 levels. Their immunocyto-
chemistry results showed that increased IL-6 was predom-
inantly co-localized with reactive astrocytes. Furthermore,
one systemic injection of neutralizing IL-6 receptor anti-
body (IL-6R Ab) abolished the SCI-induced allodynia. As
the humanized IL-6R Ab tocilizumab is approved by the
Food and Drug Administration, they proposed that toci-
lizumab may become a novel and potentially effective
means of managing SCIP. In another study, Murakami et
al. [91] reported the beneficial effects of an anti-mouse IL-
6R Ab (MR16-1) on neuropathic pain. The ELISA data
showed that IL-6 levels between 24 and 72 h after SCI
were significantly decreased in mice treated with MR16-1.
Additionally, their behavioral data suggested that MR16-1
could alleviate hyperalgesia in SCI mice. The findings from
these two studies indicate that IL-6/IL-6R trans-signaling
may be a potential target for the treatment of SCIP.
IL-6 and chemotherapy-induced peripheral
neuropathy
Chemotherapy-induced peripheral neuropathy (CIPN) is
a common consequence of several antineoplastic agents
and can severely impact patients’ long-term quality of
life [92, 93]. However, contradictory results have been
reported, and the mechanisms of CIPN have remained
unclear. In an in vivo study, three animal models of
Zhou et al. Journal of Neuroinflammation (2016) 13:141
CIPN (i.e., rats treated with cisplatin or vincristine and
mice treated with paclitaxel) were used to study the periph-
eral roles of IL-6 in painful CIPN [94]. This study first re-
ported that IL-6 treatment could prevent the painful
behavior of CIPN without interfering with the anti-tumor
activity of these chemotherapeutic regimens, suggesting a
potential neuroprotective effect of IL-6 on CIPN. In an-
other study, the role IL-6 in vincristine-induced mechanical
allodynia was examined using a mouse model of CIPN
[95]. It was found that the expression of IL-6 was increased
in CIPN mice and was co-localized with macrophage, as
indicated by double immunostaining. Moreover, IL-6 neu-
tralizing antibody considerably reduced vincristine-induced
mechanical allodynia. In addition, the incidence of
vincristine-induced mechanical allodynia was lower in IL-6
knockout mice than in wild-type mice. All of these results
suggest that IL-6 plays a vital role in vincristine-induced
mechanical allodynia. However, further investigation is re-
quired to determine whether IL-6, IL-6 neutralizing anti-
body or both can alleviate hyperalgesia and the associated
underlying mechanisms. These conflicting results may be
due to the different drug administration methods and ani-
mals used. Recently, a clinical study reported that IL-6 and
sIL-6R levels were significantly higher after the conclusion
of chemotherapy in breast cancer patients with CIPN than
in those without CIPN, providing the first clinical evidence
of the involvement of IL-6 in CIPN [96].
IL-6 and inflammatory pain
Inflammatory pain is a common clinical symptom of in-
flammatory diseases and is characterized by hyperalgesia
due to the sensitization of primary nociceptive neurons
[97, 98]. Our previous study revealed that cannabinoid
IL-6
IL-6R
gp130
gp130
JAK
p38 MAPK
PI3K
CX3CR1
TRPV1
Bone Cancer Pain
Fig. 1 Schematic representation of the downstream mechanism of IL-6 in the processing of bone cancer pain and neuropathic pain. IL-6 interleukin-6,
IL-6R interleukin-6 receptor, JAK Janus-activated kinase, PI3K phosphoinositide 3-kinase, TRPV1 transient receptor potential vanilloid channel type 1, MAPK
mitogen-activated protein kinase, STAT3 signal transducer activator of transcription 3
Page 5 of 9
CB2 receptors (CB2Rs) are involved in the anti-nociceptive
effect of electroacupuncture (EA) on inflammatory pain
[99–101]. However, it was not clear how CB2R activation
contributed to the anti-nociceptive effect of EA. Therefore,
we conducted a study to investigate the effects of CB2R ac-
tivation and EA on the expression level of several cytokines
including IL-6 in a CFA rat model of inflammatory pain
[24]. Using RT-PCR and Western blotting, we found that
the mRNA and protein levels of IL-1β, IL-6, and TNF-α
were significantly higher in CFA rats than in control rats.
Moreover, treatment with EA or the selective CB2R agonist
AM1241 significantly decreased the mRNA and protein
levels of IL-1β, IL-6, and TNF-α in CFA rats. In addition,
pretreatment with the specific CB2R antagonist AM630
significantly reversed the inhibitory effect of EA on IL-1β,
IL-6, and TNF-α in CFA rats. These results suggested that
EA suppressed the expression of IL-1β, IL-6, and TNF-α
through CB2R activation, resulting in an analgesic effect.
In another study, Sun et al. [102] found that tanshinone
IIA attenuated the development of CFA-induced mechan-
ical and thermal hypersensitivity, which was concomitant
with downregulation of the spinal IL-6 level. Recently, Xu
et al. [103] reported that triptolide, a traditional Chinese
medicine ingredient, attenuated CFA-induced inflamma-
tory pain by inhibiting spinal glia activation in rats. Pro-
inflammatory cytokine levels were significantly increased
after CFA injection. Furthermore, triptolide treatment re-
duced the levels of pro-inflammatory cytokines in the
spinal cord. These results suggested that IL-6 may play a
role in the pain-suppression effect of triptolide. More re-
cently, Yang et al. [104] explored the possible mechanisms
of the analgesic effect of oxysophocarpin, an alkaloid ex-
tracted from Sophora alopecuroides, on carrageenan
JAK
STAT3
Neuropathic Pain
Zhou et al. Journal of Neuroinflammation (2016) 13:141
PEG2
EP4R
PKA PKC ERK/MAPK
CREB NF-κB
IL-6
Neuropathic Pain
Fig. 2 Schematic representation of the possible upstream mechanism of IL-6 in the processing of neuropathic pain and inflammatory pain. PGE2
prostaglandin E2, EP4R prostaglandin E2 receptor 4, PKA protein kinase A, PKC protein kinase C, ERK extracellular signal-regulated kinase, MAPK
mitogen-activated protein kinase, CREB cAMP-response element binding protein, NF-kB nuclear factor kappa B, TNF-α tumor necrosis factor-α,
TNFR1 tumor necrosis factor receptor 1, IL-6 interleukin-6, CB2R cannabinoid CB2 receptor
induced inflammatory pain in mice. They found that IL-1β,
IL-6, TNF-α, and PGE2 was significantly higher in mice
with induced inflammatory pain than in sham mice and
that the oxysophocarpin treatment markedly decreased
their production. These findings demonstrated that IL-6
could potentially serve as a downstream target of several
drugs to relieve inflammatory pain. However, it is still un-
clear how IL-6 suppression contributes to the alleviation of
inflammatory pain. Therefore, further studies are needed
to explore the molecular and cellular mechanisms of IL-6
in inflammatory pain. Our recent studies have shown that
JAK2/STAT3 signaling may be involved.
Conclusions
By reviewing the current evidence, we discussed the rela-
tionship between IL-6 and pathological pain (Figs. 1 and 2).
These studies provided robust evidence that IL-6 plays a
critical role in the pathogenesis of BCP, neuropathic pain,
and inflammatory pain. Treatment with anti-IL-6 or anti-
IL-6R neutralizing antibody attenuates mechanical allody-
nia and thermal hyperalgesia caused by pathological pain,
indicating that inhibitors of IL-6 or its receptors may
be novel and beneficial therapeutic tools for patho-
logical pain management. Although IL-6 plays vital
roles in host defense and homeostasis maintenance, the
overproduction of IL-6 causes the onset or develop-
ment of several diseases. Therefore, novel therapeutic
strategies using IL-6 or its receptors have been developed
and successfully used for the treatment of numerous dis-
eases. It was reported that tocilizumab, a humanized
anti-IL-6R monoclonal antibody, improved the signs
and symptoms of rheumatoid arthritis [105–110], juvenile
idiopathic arthritis [111–113], and Castleman disease
Page 6 of 9
TNF-α Cannabinoids
TNFR1 CB2R
NF-κB
IL-6
Inflammatory Pain
[114–116]. Furthermore, a recent prospective comparative
cohort study provided evidence that single intradiscal in-
jection of tocilizumab exerted a short-term analgesic effect
in patients with discogenic low back pain [117]. Therefore,
inhibitors of IL-6 or its receptors may be useful for the
management of pathological pain. However, further re-
search is warranted to extensively explore the exact role of
IL-6 in pathological pain.
Abbreviations
Akt, protein kinase B; BCP, bone cancer pain; CB2Rs, cannabinoid CB2 receptors;
CCI, chronic constriction injury; CFA, complete Freund’s adjuvant; CIPN,
chemotherapy-induced peripheral neuropathy; DRG, dorsal root ganglia;
EA, electroacupuncture; ELISA, enzyme-linked immune-sorbent assay; EP4,
PGE2 receptor 4; ERK, extracellular signal-regulated kinase; gp130−/−, null
mutation of glycoprotein 130; IL-6, interleukin-6; IL-6R Ab, IL-6 receptor
antibody; JAK, Janus-activated kinase; MAPK, mitogen-activated protein
kinase; mIL-6R, membrane-bound IL-6 receptor; PI3K, phosphatidylinositol
3-kinase; PGE2, prostaglandin E2; PKC, protein kinase C; PPF, propentofylline;
PSNL, partial sciatic nerve ligation; p-STAT3, phospho-signal transducer activator
of transcription 3; rrIL-6, recombinant rat IL-6; RT-PCR, reverse transcription
polymerase chain reaction; SCI, spinal cord injury; SCN, sciatic cryoneurolysis;
sgp130, soluble form of gp130; sIL-6R, soluble form of IL-6R; TCI, tumor
cell implantation; TNF-α, tumor necrosis factor-α; TNFR1, tumor necrosis
factor receptor 1; TRPV1, transient receptor potential vanilloid channel type 1
Acknowledgements
Not applicable.
Funding
This work was supported by grants from National Natural Science Foundation
of People’s Republic China 81371250, 81400917, and 81571053, National Natural
Science Foundation of Hubei Province 2014CFB449, Shenzhen Science and
Technology Innovation Committee GJHZ20140414170821201, and Specialized
Research Fund for the Doctoral Program of Higher Education
No.20130142120102, HUST No. 2014QT021.
Availability of data and materials
The data supporting the conclusions of this article is included within the
“References” section.
Zhou et al. Journal of Neuroinflammation (2016) 13:141
Authors’ contributions
YQZ, ZL, ZHL, and SPC involved in acquisition of data, analysis of data, and
drafting of the manuscript. DWY, ML, AS, and YKT involved in study concept
and critical revision of the manuscript. YQZ, ZL, and ZHL contributed equally
to this work. All authors read and approved the final manuscript.
Competing interests
The authors declare that they have no competing interests.
Consent for publication
Not applicable.
Ethics approval and consent to participate
Not applicable.
Author details
1
Department of Anesthesiology and Pain Medicine, Tongji Hospital, Tongji
Medical College, Huazhong University of Science and Technology, Wuhan,
China. 2Department of Urology, Tongji Hospital, Tongji Medical College,
Huazhong University of Science and Technology, Wuhan, China.
3
Department of Anesthesiology, Shenzhen Second People’s Hospital,
Shenzhen, China. 4Department of Neurobiology and Key Laboratory of
Neurological Diseases of Hubei Province, Tongji Medical College, Huazhong
University of Science and Technology, Wuhan, China. 5Cancer Center, Tongji
Hospital, Tongji Medical College, Huazhong University of Science and
Technology, Wuhan, China.
Received: 7 January 2016 Accepted: 1 June 2016
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